circCACNA1D drives pulmonary fibrosis by regulating pyruvate kinase M2 dimer‑tetramer switching.

Pulmonary fibrosis is a progressive and fatal interstitial lung disease characterized by aberrant fibroblast activation and excessive extracellular matrix deposition. Circular RNAs (circRNAs) have emerged as critical regulators of fibrotic pathogenesis. However, their mechanistic roles remain incompletely defined. In the present study, circCACNA1D was identified as a novel driver of pulmonary fibrosis progression through direct interaction with pyruvate kinase M2 (PKM2). Specifically, circCACNA1D binds PKM2 and promotes its nuclear translocation and dimerization. This process is facilitated by desuccinylation at conserved lysine residues (K135, K166 and K270). The conformational shift from the tetrameric to the dimeric state reprograms cellular metabolism toward aerobic glycolysis and activates a pro‑fibrotic transcriptional program, including direct upregulation of KIF4A. In addition, the pharmacological stabilization of PKM2 tetramers with TEPP‑46 attenuated fibrotic phenotypes in vitro and alleviated bleomycin‑induced pulmonary fibrosis in mice. These findings define a previously unrecognized circRNA‑driven axis that coordinates PKM2 conformational switching, metabolic reprogramming and transcriptional activation, and suggest a potential therapeutic strategy for pulmonary fibrosis.